Mazindol combination in the treatment of attention deficit/hyperactivity

ABSTRACT

The present invention relates to the field of human health, and more particularly to the treatment of attention deficit/hyperactivity disorder (ADHD) with mazindol. The latter can be administered as monotherapy or in combination with one or more compounds, including psychostimulants, for the indication of ADHD and associated or co-morbid symptoms.

The present invention relates to the field of human health, and moreparticularly the treatment of attention-deficit/hyperactivity disorder(ADHD) with mazindol. The latter can be administered as monotherapy orin combination with one or more compounds, including psychostimulants,for the indication of ADHD and associated or co-morbid symptoms.

ADHD is a behavioural disorder that constitutes one of the mostfrequently encountered patterns in child and adolescent psychopathology.Its prevalence is estimated at 2% to 5% in the general population ofchildren of school age.

On a clinical level, this disorder combines inattention, impulsivity andmotor hyperactivity unsuited to the child's environment. Badly organisedand thoughtless, these children sometimes end up not following in class.Excessive motor agitation, incompatible with social relations andsometimes even leading to being prematurely taken out of school, isprobably the symptom that will lead the parents to consult a specialist.

The stimulating substances used, and commonly accepted in thepharmacological treatment of ADHD, in particular in children, belong toseveral pharmacological classes: psychostimulants (amphetamine,methylphenidate, bupropion), eugregorics (Modafinil, Adrafinil), andinhibitors of mono-amine oxydase B (selegiline).

The most used and best known are:

-   -   methylphenidate (MPH) is the reference treatment of ADHD in        children, adolescents and adults. It is above all a        psychostimulant known for its stimulating properties. Apart from        its dopaminergic stimulating action, on the release of        noradrenaline and dopamine, by inhibition and recapture, MPH has        no effect on the postsynaptic noradrenergic alpha-1 receptors        (modification of sensitivity).    -   amphetamine (D,L-amphetamine) has an action on the        extra-vesicular release of noradrenaline and dopamine and        therefore inhibits any form of storage. Because of potential        misuse, and undesirable peripheral effects (tachycardia, HTA,        agitation, insomnia) its medication remains very limited and        non-authorised in the majority of countries in Europe.    -   Modafinil, the authorisation of which for the treatment of ADHD        in children has just been granted recently in the United States        (2005), is a stimulating (eugregoric) medication whose action        mechanism, which is complex, is imperfectly known. Unlike MPH        and amphetamines, Modafinil does not cause dependency or        habituation. Its prescription is at the present time limited in        France to the treatment of narcolepsy and idiopathic        hypersomnia.    -   Atomoxetine, a selective inhibitor of the recapture of        noradrenaline, and a dopaminogenic stimulant (by inhibiting        recapture at the pre-frontal cortex), has demonstrated efficacy        and good tolerance in ADHD in children and adults (Spencer et        al, 1998; Popper 2000; Biederman et al, 2002). It has recently        been authorised for marketing in the United States (FDA,        November, 2002).    -   others; bupropion, caffeine, selegiline, etc.

Bupropion, a catecholamine uptake inhibitor, and an antidepressant, isalso a potential competitor in the treatment of ADHD.

Selegiline, a mono-oxidase uptake inhibitor, also has pharmacologicalproperties close to those of amphetamines. Its stimulating action in thetreatment of ADHD is known and its advantage in this use is possible.

Thus the improvement of motive hyperactivity by dopaminergenicpsychostimulants is often very significant, but neverthelessinsufficient.

This is because the stimulating substances used or which could be usedin the treatment of ADHD, in particular psychostimulants such asmethylphenidate or amphetamines, often have a short plasmatic half-life,which involves the appearance of “on-off” effects, that is to say acoming-off effect that is accompanied by a “symptom rebound” effectafter a few hours and is responsible for a worsening of the symptoms inthe last part of the night, and detrimental to the quality of fallingasleep.

In addition, some of these substances are metabolised in the organismand therefore present a toxic risk for the patient.

In addition, some of the medications administered in the treatment ofADHD are not suited to particular administration to children, especiallybecause of excessive size of the tablets or the administration of themedications several times a day.

In addition, certain particular symptoms such as insomnia, difficultiesin falling asleep, waking during the night, possibly due to excessivenocturnal motive agitation, as well as additional disorders such asinattention, impatience and impulsivity, seem to resist any form oftreatment [Chervin et al, Associations between symptoms of inattention,hyperactivity, restless legs, and periodic leg movements. Sleep 2002 15;25 (2): 213-8; Gruber et al, instability of sleep patterns in childrenwith attention-deficit/hyperactivity disorder. J Am Acad Child AdolescPsychiatry. 2000; 39 (4): 495-501].

There therefore exists a real need to develop new treatments for ADHDthat make it possible to obtain results superior to those obtained withcurrent treatments based on psychostimulants and in particular to beable to treat the symptoms that resist current treatments, without anycoming-off effect or rebound of the symptoms and presenting limitedtoxic risk. Treatments intended more particularly for children areadvantageously sought. This is the aim of the present invention.

Entirely fortuitously, studies have now shown that mazindol could, beused for the preventive and curative treatment of ADHD with significantresults, without the previously mentioned, drawbacks of the othersubstances, in particular certain psychostimulants.

Mazindol has the following chemical formula:

5-(4-chlorophenyl)-2,5-dihydro-3H-imadazo[2,1-a]isoindol-5-ol

Mazindol is considered, in current medication classifications, as apsycoanaleptic and anorexigenic medication, but also as giving rise towakefulness, currently not authorised in France, or only authorised byTAU (temporary authorisation for use) in obesity and narcolepsy. It isan advantageous chemical compound for dealing with malfunctioning ofwakefulness mechanisms.

The essential pharmacological action of mazindol, in all speciesstudied, in healthy animals and in humans, is hypothalamic, on theappetite-regulating dopaminogenic centres (Hadler, 1972). Its principalmetabolism is urinary (¾ urine, ¼ faeces).

Mazindol is a non-amphetamine compound because of its tricyclic chemicalstructure. It offers a pharmacological profile very close to that ofamphetamines without reproducing the secondary effects thereof. Thus,unlike amphetamine molecules, mazindol increases motor activity only inrelation to extension of the duration of wakefulness and does not causecardiovascular modifications or stereotypes (Kadler, 1972).

In addition, in animal toxicology studies, the toxic potential ofmazindol has proved to be very low. This is because mazindol presents alimited toxic risk since the metabolites of mazindol are excreted in theurine. In particular:

-   -   no carcinogenic effect;    -   no mutagenic effect;    -   no toxicology effect in reproduction were observed.

In addition, mazindol has a long plasmatic half-life time, greater thanone day, which avoids the appearance of coming-off effects, andtherefore an effect of “symptom rebound” at the end of the day.

In fact, after single or repeated oral administration, mazindol isabsorbed with a tmax of 2-4 hours. Taking food concomitantly is liableto delay absorption (by approximately 1 hour), but does not modify thetotal quantity absorbed. The plasmatic half-life time is reached after33-55 hours.

The pharmacokinetics is linear (independent of the dose) for doses ofbetween 1 mg/day and 4 mg/day, and 75% of the dose is still“plasmatically” effective 24 hours after taking.

In addition, mazindol (Teronac®) tablets are small and therefore do notpose any problem in administration. For pharmacokinetic reasons, alreadycited, mazindol is administered only once a day, which limitsconstraints for the patient, and in particular in the special case ofchildren for the school, which is often requested to perform the middayadministration.

Mazindol has for more than 30 years been the subject of many doubleblind control studies against a placebo on the treatment of obesity inadults. Studies in the treatment of narcolepsy and hypersomnia arelimited. On the other hand, safety in use in the short, medium and longterm in the treatment of excessive daytime somnolence associated withnarcolepsy and idiopathic hypersomnia is relatively well documented forthe time (Shindler et al, 1985).

Mazindol has in these two disorders (narcolepsy and hypersomnia) becomea TAU (Temporary Authorisation for Use) treatment by third intentionthat significantly improves the quality of life of the patient, havingdifficulty in keeping awake.

The object of the present invention is therefore the use of mazindol forthe preparation of a medication intended for the preventive and/orcurative treatment of attention-deficit/hyperactivity disorder (ADHD) orat least one of its symptoms, in a patient in need of such treatment.

In the context of the present invention, the diagnosis ofattention-deficit/hyperactivity disorder (ADHD) is based on the clinicalcharacteristics defined by the international classification, DSM/IV(Diagnostic and Statistical Manual of Mental Disorders, 4th ed, 1994).

The criteria of DSM-IV includes three dimensions (inattention,impulsivity and hyperactivity), normal intellectual efficiency (IQ>80,with an age between 5 and 12 years) and having isolated iron deficiency,but not anaemic, that is to say having a normal haemoglobin level. Theexpression “iron deficiency” means hypoferrinaemia without significantmodification to the serum concentration of soluble transferrinreceptors.

The patient according to the invention is chosen from among a newbornbaby, a child, an adolescent and an adult. According to a preferentialembodiment, it is a case of a child aged approximately 5 to 12 years,and/or for an adolescent. The patient according to the inventionadvantageously suffers iron deficiency, but is not anaemic. Ferritindeficiency can be measured in the serum, but also in all otherbiological fluids such as the cerebrospinal fluid.

A ferritin deficiency corresponds to a serum concentration of ferritinin the adult patient of less than approximately 50 μg/litre. Thishypoferritinaemia may reach ferritin concentrations of less thanapproximately 40 μg/l, or even less than approximately 35 μg/l, lessthan 30 μg/l, less than 20 μg/l, less than 15 μg/l, or even less thanapproximately 10 μg/l. The techniques of determining serum ferritin arewell known to persons skilled in the art. The immunoenzymatic method(IMX ferritin kit, Abbot Laboratories) can be cited.

The patient according to the invention also has a normal serumconcentration of receptors soluble to transferrin. Transferrin isinvolved in the acquisition of iron by the cells of the organism; thisacquisition is controlled by the number of transferrin receptorsexisting on the cell surface. The concentration of these receptors canbe evaluated by techniques known to persons skilled in the art such asnephelemetry (Ruivard et al. 2000 Rev Méd Interne 21: 837-843). A normalrange of concentration of receptors soluble to transferrin is 2.0-4.50mg/l for men and 1.80-4.70 mg/ for women (see RsTF kit Ref 2148315 fromRoche).

The compounds or compositions according to the invention can beadministered in various ways and in different forms. Thus they can beadministered systemically, orally, anally or parentally, in particularby inhalation or injection, such as for example by intravenous,intramuscular, subcutaneous, transdermal or intra-arterial method.Preferably it is orally.

For injections, the compounds are generally packaged in the form ofliquid suspensions, which may be injected by means of syringes orperfusions for example. In this regard the compounds are generallydissolved in saline, physiological, isotonic, buffer, etc., solutions,compatible with pharmaceutical usage and known to persons skilled in theart. Thus the compositions may contain one or more agents or vehicleschosen from dispersants, solubilisers, stabilisers, preservatives, etc.Agents or vehicles that can be used in liquid and/or injectableformulations are in particular methylcellulose, hydroxymethyl cellulose,carboxymethylcellulose, polysorbate 80, mannitol, gelatine, lactose,vegetable oils, acacia, etc.

The compounds can also be administered in the form of gels, oils,tablets, suppositories, powders, capsules, aerosols, etc, possibly bymeans of galenic forms or devices providing prolonged and/or delayedrelease. For this type of formulation, use is advantageously made of anagent such as cellulose, carbonates or starches.

“ADHD symptom” designates in particular attention disorders such asinattention, impulsivity, impatience, oppositional disorders, but alsodaytime or night-time motor hyperactivity, restless legs syndrome, andinsomnia.

Insomnia designates:

a. onset insomnia that is characterised by difficulties in fallingasleep;

b. maintenance insomnia that is characterised by night-time motorhyperactivity and waking up during the night, and

c. psychopathological insomnia, generally chronic and generally linkedto anxiety, stress and depressive episodes.

According to another aspect of the present invention, mazindol is usedin combination with iron as a combination product for simultaneous,separate or sequential use.

According to a preferred method of use, the iron is used as a supplementwith the patient before the administration of mazindol.

Within the meaning of the present invention, “iron” means iron in theform of an iron atom, iron salt or organic iron, or any formulationcontaining iron that is pharmaceutically acceptable. By way of anon-exhaustive list, the pharmaceutically acceptable iron salt isselected from ferrous salts and ferric salts, preferably from ferricammonium citrate, ferric pyrophosphate, ferrocholinate, ferrousabscorbate, ferrous aspartate, ferrous chloride, ferrous sulphate,ferrous tartatrate, ferrous fumatrate, ferrous gluconate, ferrousgluceptate, ferrous sulphate glycine, ferrous lactate, ferrous oxalateand ferrous succinate.

According to a preferred embodiment of the invention, the iron salt isferrous sulphate, and preferably gastro-protected ferrous sulphate.

Alternatively, the pharmaceutical acceptable iron is in the form ofdextran iron, sucrose iron, poly-maltose iron, or sorbitol iron. Whenthe iron is in the form of pharmaceutically acceptable organic iron, itis preferably iron biglycinate, iron glycinate or iron proteinsuccinylate.

According to a preferred embodiment, the use of mazindol possibly inassociation with the iron according to the invention is implemented incombination with at least one compound selected from psychostimulants,as a combination product for simultaneous, separate or sequential use.

Psychostimulant compounds designate dopamine and/or noradrenaline uptakeinhibitors and agonists of catecholamines. Among these, the followingcan be cited non-exhaustively:

1) psychostimulant compounds: methylphenidate (speciality Ritalin,Concerta, Equasym), modafinil (Sparlon, Modiodal, Provigil), atomoxetine(Strattera), and amphetamines such as d-amphetamine, dexadrine anddexamphetamine.

2) L-Dopa: Modopar, Sinemat

3) selective dopamine agonists: pramipexole (Sifrol, Mirapex),ropinirole (Requip, Adartrel), lisuride, pergolide, cabergoline, etc.

The role of iron with regard to the central nervous system is oftenreported in fundamental neurophysiopathology as clinical. Functionalintellectual asthenia, chronic fatigue syndrome, or converselypsychomotive instability and irritability may be the consequence of irondeficiency (Lozofff, 1989 Adv Pediatr 1989; 6: 331-59). The role of ironin the physiopathology of neurological ailments, and in particular inidiopathic Parkinson's disease, has been known for more than thirtyyears. The evidence of an increase in iron in particular in certaincerebral structures (e.g. dentate nucleus) in rare neurodegenerativepathologies (e.g. Friedreich's ataxia) is also known. More recently, therole of transferrin receptors in certain neuropathological processes hasjust been documented (Marder F et al, 1998 Neurology 50, 4: 1138-40). Anincrease in number of transferrin receptors in cells of the endotheliumof the cerebral capillaries could be responsible for the accumulation ofbasal ganglia (globus pallidus, substantia nigra, red nucleus anddentate nucleus). A malfunctioning of the transferrin receptors byhyperplasia (increase in the number of receptors) at a central levelwould explain the accumulation of iron in certain structures involved inphenomena of neurodegenerescence. On the other hand, a reduction inthese receptors would contribute to protecting the central nuclei fromthe phenomenon. On the assumption of a decrease in plasma ferritin inADHD physiopathology, a physiological increase in the transferrinreceptors should occur, as occurs normally in cases of anaemia, in ordernot to put the cerebral structures in iron deficiency. On the otherhand, an absence of response (an absence of increase in the number oftransferrin receptors) would lead to a cerebral iron reduction and wouldbe compatible with dopamine malfunctioning by reducing its synthesisand/or stimulating the dopaminergic receptors. The present inventiontherefore also concerns the use of mazindol, optionally in associationwith iron or one of its pharmaceutically acceptable salts, and/or apsychostimulant for the preventive treatment of a newborn, infant,adolescent or young adult patient caused to develop a neurodegenerativepathology at an adult age, characterised in that the said newborn,infant, adolescent or young adult patient has at least the followingsymptoms:

-   -   ferritin deficiency, so that the serum concentration of ferritin        is less than 50 μg/l;    -   a normal serum concentration of receptors soluble to        transferrin;    -   attention-deficit/hyperactivity disorder, or at least one of its        symptoms.

Preferably the said patient is a child with an IQ>80, aged betweenapproximately 5 and 12 years and non-anaemic.

Preferably the said neurodegenerative pathology is Parkinson's disease,cerebellar ataxia, Friedreich's ataxia, Alzheimer's disease,Huntingdon's chorea or amyotrophic lateral sclerosis. More particularly,it is Parkinson's disease.

In particular, when mazindol is used in association with ferroussulphate, the quantity of ferrous sulphate administered to the patienton a daily basis is between 0.1 mg and 10 mg, preferably between 100 mgand 2 g per day, preferably approximately 500 mg, in one or more doses.

More particularly, according to the present invention, the patientsundergo iron supplementation, in particular ferrous sulphate, for 12weeks and the treatment with mazindol for 12 weeks.

The dosage corresponds to a daily dose of mazindol preferably between 1and 2 mg (recommended doses in the treatment of narcolepsy in adults).

The criteria for evaluating the efficacy of the treatment ofattention-deficit/hyperactivity disorder by mazindol optionally inassociation with iron and/or a psychostimulant in the treatment ofattention-deficit/hyperactivity disorder according to the presentinvention are the reduction (>30%) in the rating scale severity scorefor attention-deficit/hyperactivity symptoms AHD-RS (after 12 weeks oftreatment, and an improvement in severity scores for Conner's Parentquestionnaire (CPRS), Conner's Teacher questionnaire (CTRS) and CGI(clinical global impressions). Subjective somnolence is assessed usingthe CASS scale (child and adolescent somnolence scale). The quality offalling asleep is assessed by means of the restless legs syndromeseverity scale.

Finally, the present invention also concerns a pharmaceuticalcomposition comprising pharmaceutically acceptable excipients andmazindol for the preventive and/or curative treatment of ADHD or one ofits symptoms.

According to the present invention, the composition may also compriseiron or one of its pharmaceutically acceptable salts and/or apsychostimulant.

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1. A method of treating attention-deficit/hyperactivity disorder (ADHD)according to DSM IV criteria without any coming-off effect or rebound,comprising administering an effective amount of mazindol to a patient inneed of such treatment. 2-15. (canceled)
 16. The method according toclaim 1, wherein said patient is chosen from a newborn baby, a child, anadolescent, and an adult.
 17. The method according to claim 16, whereinsaid patient is a child having isolated iron deficiency, but notanaemic.
 18. The method according to claim 1, wherein mazindol isformulated to allow its administration by oral, anal, parenteral,infra-muscular, or intravenous method.
 19. The method according to claim1, wherein the dosage of mazindol corresponds to a daily dose ofmazindol of between 1 and 2 mg.
 20. The method according to claim 1,wherein said patient suffers from ferritin deficiency, said serumferritin concentration of said patient being less than 50 μg/l, lessthan approximately 40 μg/l, less than approximately 35 μg/l, less thanapproximately 30 μg/l, less than approximately 20 μg/l, less thanapproximately 15 μg/l, less than approximately 10 μg/l, or less thanapproximately 5 μg/l.
 21. The method according to claim 20, wherein saidpatient also has a normal serum concentration of transferrin solublereceptors.
 22. The method according to claim 1, wherein the patient is anewborn, adolescent or young adult having at least one of the followingsymptoms: a ferritin deficiency, so that the serum ferritinconcentration is less than 50 μg/l; a normal serum concentration oftransferrin-soluble receptors; or attention-deficit/hyperactivitydisorder according to DSM IV criteria.
 23. A method of treatingattention-deficit/hyperactivity disorder (ADHD) according to DSM IVcriteria, comprising administering an effective amount of mazindolsimultaneously, separately or sequentially with iron to a patient inneed of such treatment.
 24. The method according to claim 23, whereinthe patient is chosen from a newborn baby, a child, an adolescent, andan adult.
 25. The method according to claim 24, wherein the patient is achild having isolated iron deficiency, but not anaemic.
 28. The methodaccording to claim 23, wherein mazindol is formulated to allow itsadministration by oral, anal, parenteral, intra-muscular or intravenousmethod.
 27. The method according to claim 23, wherein the dosage ofmazindol corresponds to a daily dose of mazindol of between 1 and 2 mg.28. The method according to claim 23, wherein the patient suffers fromferritin deficiency, wherein the serum ferritin concentration of thepatient is less than 50 μg/l, less than approximately 40 μg/l, less thanapproximately 35 μg/l, less than approximately 30 μg/l, less thanapproximately 20 μg/l, less than approximately 15 μg/l, less thanapproximately 10 μg/l or less than approximately 5 μg/l.
 29. The methodaccording to claim 28, wherein the patient also has a normal serumconcentration of transferrin-soluble receptors.